Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury

Lai, Yuping, et al. 2009. Nat. Med., 15: 1377-1383.

Student: Chia-Hui Huang (黃佳慧)                       Time: 14:10~15:00, Apr. 14, 2010

Commentator: Dr. Lien-I Hor (何漣漪老師)      Place: Room 601

Abstract:

        Staphylococcus epidermidis is a commensal bacterium on the human skin. They usually do not initiate inflammation or cause disease in contact with keratinocytes in the epidermis, but induce inflammation after penetrating the epithelial barrier [1]. During wound repairing, uncontrolled immune response is undesirable. Hence, normal immune defense requires to maintain a balance by minimizing unnecessary inflammation but rapidly responding to infection and injury. Toll-like receptors (TLRs) are responsible for the detection of microbes and regulating inflammation. The authors wanted to know how S. epidermidis influences the inflammatory response of keratinocytes through negative regulation of TLR signaling. After treating human normal keratinocytes with poly(I:C) to stimulate TLR3, the IL-6 and TNF-a expression was increased, which was suppressed by the <10-kDa product of S. epidermidis. Ears of mice pretreated with the <10-kDa product of S. epidermidis before poly(I:C) treatment showed less inflammation and a decrease in the IL-6 and TNF-a expression. To investigate whether TLR3 might be activated by damaged cells, the authors made incisions on the backs of mice and found that Tlr3^−/− mice produced less IL-6 and TNF-a at the wound edge than the wild-type controls. They further induced human keratinocytes to undergo apoptotic and necrotic cell death by ultraviolet B radiation. The RNA released from propidium iodide–positive necrotic cells increased TNF-α release and TLR3 expression in keratinocytes. Lipoteichoic acid (LTA) is a major constituent of the cell wall of Gram-positive bacteria, including S. epidermidis. They found that LTA inhibited poly(I:C)-induced TNF-α production. Using a specific neutralizing antibody, they confirmed the identity of LTA as the <10-kDa product of S. epidermidis. Moreover, LTA induced TRAF1 expression which was processed by caspase-8 to an active N-TRAF1 followed by binding to TRIF to mediate inhibition of TLR3. In Traf1^−/− mice, LTA was unable to suppress the IL-6 and TNF-α production at the wound edge. Furthermore, the expression of TRAF1 decreased in Tlr2^−/− or Myd88^−/− mice exposed to LTA, which suggested that LTA inhibited inflammatory cytokine release and inflammation triggered by injury through a TLR2-dependent mechanism. Taken together, these findings show that commensal bacteria have potential benefit on skin by modulating cutaneous inflammatory responses.

Reference:

1.      Michael Otto. 2009. Staphylococcus epidermidis — the ‘accidental’ pathogen. Nat. Rev. Microbiol., 7: 555-567.